Project Summary My laboratory recently uncovered an unexpected and intriguing role for mature adipocytes during skin wound healing: control of inflammation after injury. In particular, we identified that mature adipocytes undergo lipolysis to release of lipids into wound beds to initiate inflammation. Our findings are important for several reasons. First, adipocytes have been shown to improve wound healing and scarring yet how mature adipocytes function in this process is unclear. Second, the release of lipids from adipocytes, or lipolysis, has been shown to modulate inflammation in traditional depots, yet whether skin adipocytes regulate the essential inflammatory processes following skin injury is not known. Furthermore, adipocytes and their derivatives (fatty acids and/or cytokines) are a tractable cell type to create a personalized therapy to promote healing in patients with chronic wounds. Finally, glucocorticoids are known to influence adipocyte biology and also to inhibit wound healing, but whether the effect of glucocorticoids on wound healing is mediated through adipocytes is not known. Through three focused and complementary Specific Aims, the work proposed in this application will take advantage of multiple genetic mouse models that allow specific depletion of adipocytes, adipocyte lipolysis, lipidomics, lipid tracking, bioengineered tissue models, and a novel bioanalytical assay platform to define the function adipocyte-derived lipids during skin injury and how these are altered with glucocorticoids, age, diabetes and obesity. We will (1) identify the role of adipocyte derived lipids during inflammation during skin wound healing, (2) determine whether glucocorticoids influence wound healing through depletion of lipids from mature, dermal adipocytes, (3) define whether adipocyte fatty acids can modulate wound healing in aged and diabetic mice or are altered in human skin. These studies will identify specific pro-healing cell populations and molecules that can be utilized to promote healing in human patients with defective wound healing or other skin disorders.